Investigations of human platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal-derived cells in culture, have provided a rational basis for the understanding of at least one mechanism involved in malignant transformation. PDGF is a heat-stable (100~C), cationic (isoelec-tric point 9.8) polypeptide that circulates in blood stored in the alpha-granules of platelets. It is released from platelets into the serum during blood clotting, constituting the major polypeptide growth factor of serum. It is suggested that in vivo, PDGF is delivered during platelet degranulation at the site of injury where it participates in the process of wound healing by stimulating the proliferation and migration of connective tissue cells. We have shown recently that PDGF and the transforming protein of the simian sarcoma virus (SSV), an acute transforming retrovirus of primate origin, derive from the same or closely related cellular genes. This conclusion is based on the demonstration that PDGF and the SSV-transforming protein share extensive amino acid sequence homology, have common antigenic determinants and structural conformation, and exert identical biological functions. These findings suggest that the ability of the simian sarcoma virus to induce transformation derives from the incorporation of the PDGF gene within the retroviral genome. The resulting transforming onc gene (v-sis) region within the retrovirus genome codes for a PDGF-like mitogen and is capable of inducing neoplastic transformation by the continuous production of this potent mitogen, causing sustained cell proliferation. Consistent with the findings described above is the detection of v-sis-related messenger RNAs in human tumors of mesenchymal origin, such as glioblastomas, fibrosarcomas, and osteosarcomas. Production of PDGF-like mitogen by these human malignant cells in culture has been established. More recent studies have demonstrated that these cells synthesize, process, and release PDGF-like polypeptides which are recognized by specific PDGF-antisera. These findings demonstrate that activation of sis transcription can cause the sustained abnormal proliferation of human cells which are target cells of PDGF action. Thus, sis activation may be involved in the process leading normal cells of mesenchymal origin toward malignancy. (J)